Association between immune check point inhibitors and digestive system inflammatory adverse reactions: evidence from pharmacovigilance analysis and systematic review.

Abstract

<h4>Purpose</h4>Comparative real-world data on the spectrum of digestive inflammatory adverse reactions across ICI classes are limited. Existing evidence on immune-related Sjögren's syndrome/sialadenitis consists largely of case reports and small series.<h4>Methods</h4>We performed disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) database (2015-2023) to evaluate associations between ICIs and digestive inflammatory adverse reactions. Additionally, we conducted a systematic review up to July 2025 to identify published cases of ICI-associated Sjögren's syndrome/sialadenitis.<h4>Results</h4>PD-1 inhibitors (pembrolizumab and nivolumab) showed the strongest associations with immune-mediated oesophagitis and gastritis. Pembrolizumab was also highly associated with hepatobiliary events, including immune-mediated cholangitis (ROR 249.18, 95% CI 169.04-367.32) and hepatitis (ROR 85.51, 95% CI 73.22-99.86). In contrast, the CTLA-4 inhibitor ipilimumab exhibited the strongest signal for immune-mediated enterocolitis. Atezolizumab and ipilimumab were significantly associated with spontaneous bacterial peritonitis. Our systematic review identified 93 cases of ICI-associated Sjögren's syndrome/sialadenitis, predominantly in patients with melanoma or lung cancer receiving PD-1 inhibitors.<h4>Conclusion</h4>PD-1 inhibitors are more strongly associated with upper GI and hepatobiliary inflammatory adverse reactions, whereas CTLA-4 inhibitors carry a higher risk of enterocolitis. These findings underscore the need for ICI-specific monitoring protocols. Early recognition and tailored management-including potential treatment interruption or corticosteroid use-are critical to minimizing severe outcomes. Clinicians should maintain a high index of suspicion for rare inflammatory adverse reactions such as sialadenitis, even as incidence remains low. These insights support more personalized risk-benefit assessment and inflammatory adverse reactions management in patients receiving ICIs.